The purpose of this project is to determine intermolecular interactions between sickle cell hemoglobin (Hb S) molecules which are in the unliganded conformation (T-state). X-ray diffraction patterns show that deoxy-Hb S polymerizes into microtubular structures of surface diameter of about 170 A, with a core of low electron density of approximate diameter of 55 A. The meridional spacings, parallel to the fiber axis are 1/64 A. Contact regions between molecules can be found from the orientation of the molecule in the microtubular structure. Two orientational parameters may be obtained from the available X-ray diffraction data by systematically varying the orientation of the hemoglobin molecule in two dimensional angular space. The value of the Fourier transforms for each orientation is then compared with those observed on the diffraction patterns. The third angular parameter of molecular orientation may be obtained by resorting to model building with computer graphics. For this approach one of the questions to be answered is whether the primary determining mutational site is in contact along the longitudinal or lateral direction of the filaments or possibly in both. Because of the knowledge of the molecular architecture of hemoglobin, it becomes possible to determine all other regions of contact by ascertaining one such contact. This information about intermolecular contact regions and their conformations should suggest possible modifications of the hemoglobin surface, which in turn may prevent sickling of susceptible erythrocytes.